This invention provides methods for treating inflammatory conditions, including but not limited to, inflammatory bowel disease (ulcerative colitis, Crohn""s disease, and proctitis), other noninfectious, inflammatory conditions of the GI tract (microscopic colitis, allergic eosinophilic gastroenteritis, food allergies, pill induced esophagitis, celiac disease, recurrent polyps, and hemorrhoids), and psoriasis using progesterone and progesterone analogs.
xe2x80x9cInflammatory bowel diseasexe2x80x9d (IBD) encompasses the idiopathic, chronic inflammatory bowel diseases ulcerative colitis (UC), Crohn""s disease (CD), and proctitis. Researchers do not know the cause of these diseases, but believe that they involve genetic and immunologic influences on the gastrointestinal tract""s ability to distinguish foreign from self-antigens and/or to alter the mucosal immune response. They share many overlapping epidemiological, clinical, and therapeutic features. IBD affects up to 1,000,000 Americans and disease symptoms can be so severe as to prevent the patient from carrying on a normal life. The total cost of the disease, including lost productivity, in the US is two billion dollars per year. Ward et al., Clinical economics review: medical management of inflammatory bowel disease, Ailment Pharmacol Ther 13:15-25 (1999). Drug therapies that allow patients to avoid surgical intervention could reduce the cost significantly.
IBD (UC, CD, and proctitis) is different from spastic colon or irritable bowel syndrome, which is a motility disorder of the gastrointestinal tract. UC is characterized by a diffuse, continuous, superficial, ulcerative inflammation of the colon, not due to any known single cause. The inflammation often begins within the rectum and extends proximally into the bowel. UC affects the inner mucosal layer of the colon (lamina propria) in a continuous manner, with no portions of healthy tissues between the diseased areas. Additionally, it affects only the colon, not other areas of the gastrointestinal (GI) tract, except in rare instances. UC may be accompanied by bloody diarrhea, constipation, very frequent bowel movements (often 15 to 20 per day), explosive diarrhea, rectal incontinence, pus, mucus, gas, fever, tachycardia, weakness, and anemia. UC creates striking changes in the mucosa and submucosa of the colon and rectum. The disease causes diffuse severe ulceration, inflammation, and congestion of the lining of the colon and rectum. More severe disease states include thinning of the bowel, susceptibility to ulcers, fibrosis, contraction, and narrowing of the intestinal lumen.
CD is characterized by focal, asymmetric, transmural inflammation affecting any portion of the gastrointestinal tract from the mouth to the anus. The ileum and right colon are, however, most often involved. CD affects all layers of the intestine, but there can be patches of normal bowel in between the diseased regions. Depending on where in the bowel the disease manifests itself, CD can cause nausea vomiting, epigastric pain, diarrhea, cramping abdominal pain, rectal bleeding, loss of appetite, fever, night sweats, malaise, arthralgias, and weight loss.
Proctitis, inflammation of the rectum, is invariably present in UC and is sometimes present in CD. It may also occur independently from these diseases. Proctitis is another manifestation of IBD with pathology similar to UC. A patient presenting with proctitis may later develop full-blown UC or CD.
Physicians and medical researchers have not been successful in identifying a cause for these diseases, although several theories have been postulated. The diseases may be caused by a pathogen or other antigen that initiates the inflammatory response in the bowel, accompanied by a defect in the ability to down-regulate the immune response. Once initiated, many of the pathophysiological events in IBD are related to amplification of the inflammatory process. In response to antigens, cytokines and other inflammatory mediators are released. Some cytokines promote T cell activity. The inflammatory cascade continues with IL-2, helper T cells, B-cell proliferation, and antibody synthesis. Stimulated neutrophils and macrophages accumulate and further damage the tissue by releasing reactive oxygen species and other biologically active products. Additional acute inflammatory cells respond to the tissue damage, whether or not the primary initiating stimulus has ceased.
Other research on IBD suggests that abnormalities in the immune system, nonimmune cells in the intestinal mucosa, genetic risk determinants, and random environmental factors may all be necessary to induce IBD. Papadakis et al., Current Theories on the Causes of Inflammatory Bowel Disease, Gastroenterol Clin North Am 28:283-296 (1999). Researchers have also postulated that tumor necrosis factor-xcex1 (TNF-xcex1), a proinflammatory cytokine, may play an important role in the pathogenesis of inflammatory bowel disease. Sanborn et al, Antitumor necrosis factor therapy for inflammatory bowel disease: a review of agents, pharmacology, clinical results, and safety, Inflamm Bowel Dis 5:119-33 (1999). The uncertainty about the cause of IBD has lead to confusion about the appropriate treatment strategy.
Currently, no treatment exists that will cure or effectively manage both forms of inflammatory bowel disease. Present treatments include aminosalicylates (sulfasalazine, mesalamine), glucocorticoids (hydrocortisone, prednisone), antibiotics (to reduce secondary infection), immunosuppressants (6-mercaptopurine, cyclosporine), belladonna, atropine, and phenobarbital. Immunosuppressants (6-mercaptopurine, azathioprine, FK-506/tacrolimus) and neuroimmunomodulation agents (somatostatin, substance P, local anesthetics) have also been used as therapy for IBD. Prevention of adhesion and recruitment has been suggested by using antisense oligonucleotides to ICAM-1. Other miscellaneous therapies that have been suggested include arachidonic acid metabolites, anti-free radicals, short-chain fatty acids, nicotine, bismuth, ketotifen, heparin, interferon-xcex1, chloroquinone/hydroxychloroquine, hyperbaric oxygen, IV immunoglobulin, and leukapheresis. Sands, Novel Therapies for Inflammatory Bowel Disease, Inflammatory Bowel Disease 28:323-351 (1999).
Infliximab, an anti-TNF-xcex1 antibody, has recently been developed as a treatment for Crohn""s disease, because overproduction of TNF-xcex1 leads to inflammation. Biological activities attributed to TNF-xcex1 include induction of pro-inflammatory cytokines such as IL-1 and IL-6, enhancement of leukocyte migration by increasing endothelial layer permeability and expression of adhesion molecules by endothelial cells and leukocytes, and activation of neutrophil and eosinophil functional activity. REMICADE(trademark) (Infliximab) Prescribing Information.
Additional medical management strategies include psychotherapy, diet control, fluid and electrolytes. A significant number of patients must resort to surgical removal of the affected portion of the bowel. None of the known therapies provide successful long term treatment for all patients, and many of the therapies have serious side effects. For example, patients treated with steroid drugs, such as glucocorticoids, can develop diabetes, hypertension, psychological changes, Cushings syndrome, changes in protein metabolism, osteoporosis, cataracts, avascular hip necrosis, and infection. Patients taking immunosuppressants run serious risk of infection and may have an increased incidence of cancer.
Improved treatments are also needed for other noninfectious, inflammatory conditions of the GI tract, including but not limited to microscopic colitis, allergic eosinophilic gastroenteritis, food allergies, pill induced esophagitis, celiac disease, recurrent polyps, and hemorrhoids.
Microscopic colitis is another form of colitis, where only microscopic changes are seen in the GI tract tissue. No gross clinical manifestations are visible upon colonoscopy. Patients with microscopic colitis commonly have diarrhea.
Allergic eosinophilic gastroenteritis can be diagnosed upon biopsy of the GI tract tissue, which will show predominantly eosinophilic infiltration of the bowel wall. This inflammatory condition is induced by an allergic reaction to food, microbes, or other ingested substance that come in contact with the bowel wall. Cramping pain, diarrhea, and weight loss are common. This condition is often treated with prednisone. Food allergies can also cause other inflammatory conditions in the GI tract, and are often treated with steroid hormones, such as the glucocorticoids.
Pill-induced esophagitis is an inflammatory condition of the esophagus caused when a pill becomes lodged in the esophagus during swallowing. The inflammatory condition can continue even after the pill becomes dislodged.
Celiac disease is an inflammatory condition of the small intestine, precipitated by the ingestion of wheat, rye, and barley, in individuals sensitive or allergic to these foods. While sensitive individuals can try to avoid these foods, it is very difficult to prevent accidental ingestion, and patients very often require treatment. Symptoms of celiac disease include diarrhea, bloating, and discomfort.
Recurrent polyps are also thought to have an inflammatory component, with inflammation in the colon and around the polyps. Polyps are a serious, precancerous GI condition, and are generally removed surgically. A treatment is needed to prevent polyps from recurring or treat them without surgical intervention.
Hemorrhoids, enlarged and inflamed veins in the wall of the anus, are usually a consequence of prolonged constipation or diarrhea. The inflammatory process affects the veins and the tissues surrounding the veins. Hemorrhoids can occur with IBD (UC, CD, and proctitis) and may also occur independently of these diseases. This inflammatory condition of the GI tract can be treated with anti-inflammatory steroid drugs, such as glucocorticoids, or surgery.
Psoriasis, another inflammatory condition, affects more than 7 million Americans. It is a noncontaigious skin disorder that most commonly appears as inflamed swollen skin lesions covered with silvery white scale. The exact cause of psoriasis is not known, but a patient""s keratinocytes grow as if there was a wound, in a regenerative maturation process. The skin cannot shed the extra cells fast enough, and excessive skin cells build up and form elevated, scaly lesions. Psoriasis occurs in several forms including: plaque psoriasis, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, pustular psoriasis, psoriatic arthritis, scalp psoriasis, and nail psoriasis.
Various treatment strategies have been used for psoriasis, though none are completely effective. Topical steroid medications are one of the most common therapies prescribed. Steroids can also be injected into the lesions. Topical retinioids have also been useful. Phototherapy offers a second level of treatment for more persistent cases. The third level of treatment includes systemic drugs such as methotrexate, oral retinoids, and cyclosporin.
Recent research has suggested that psoriasis may respond to treatment with an anti-TNF-xcex1 monoclonal antibody. Oh, C. J., et al., Treatment with anti-tumor necrosis factor alpha (TNF-xcex1) monoclonal antibody dramatically decreases the clinical activity of psoriasis lesions, J. Am. Acad. Dermatol., 42:829-30 (2000). Elevated levels of TNF-xcex1 have been associated with psoriasis, especially psoriatic arthritis and psoriasis vulgaris. Ritchlin C., et al., Patterns of cytokine production in psoriatic synovium, J. Rheumatol., 25:1544-52 (1998); Okubo Y, et al., Peripheral blood monocytes in psoriatic patients overproduce cytokines, J. Dermatol. Sci., 17:223-32 (1998).
Medroxyprogesterone acetate is a derivative of progesterone and is a white, odorless crystalline powder, stable in air, melting between 200xc2x0 and 210xc2x0 C. The chemical name for medroxyprogesterone acetate is pregn-4-ene-3,20-dione, 17-(acetyloxy)-6-methyl-, (6xcex1)-. Its structural formula is as follows: 
Medroxyprogesterone acetate is currently prescribed for secondary amenorrhea, abnormal uterine bleeding due to hormonal imbalance, and contraception. Medroxyprogesterone acetate has also been combined with estrogens for treatment of menopausal symptoms. Medroxyprogesterone acetate, acting through its regulation of the menstrual cycle, can also be used for reduced iron-deficiency anemia, protection against pelvic inflammatory disease, protection from endometrial cancer, and improved hematologic parameters among users with sickle cell disease. Cullins, Noncontraceptive Benefits and Therapeutic Uses of Depot Medroxyprogesterone Acetate, Joumal of Reproductive Medicine, 41:428-433 (1996). Thus, it is surprising that the administration of progesterone or progesterone analogs is effective in the treatment of inflammatory conditions, including but not limited to, inflammatory bowel disease (ulcerative colitis, Crohn""s disease, and proctitis), other noninfectious, inflammatory conditions of the GI tract (microscopic colitis, allergic eosinophilic gastroenteritis, food allergies, pill induced esophagitis, celiac disease, recurrent polyps, and hemorrhoids), and psoriasis.
It is an object of the present invention to provide a method for treating a patient suffering from at least one of the following conditions: inflammatory conditions, including but not limited to, inflammatory bowel disease (ulcerative colitis, Crohn""s disease, and proctitis), other noninfectious, inflammatory conditions of the GI tract (microscopic colitis, allergic eosinophilic gastroenteritis, food allergies, pill induced esophagitis, celiac disease, recurrent polyps, and hemorrhoids), and psoriasis wherein a progesterone or progesterone analog is administered to the patient.
It is an object of the present invention to provide a method for treating a patient suffering from inflammatory conditions, including but not limited to, inflammatory bowel disease (ulcerative colitis, Crohn""s disease, and proctitis), other noninfectious, inflammatory conditions of the GI tract (microscopic colitis, allergic eosinophilic gastroenteritis, food allergies, pill induced esophagitis, celiac disease, recurrent polyps, and hemorrhoids), and psoriasis, wherein medroxyprogesterone acetate is administered to the patient.
The present invention relates to a method for treating a patient suffering from at least one of the following inflammatory conditions, including but not limited to, inflammatory bowel disease (ulcerative colitis, Crohn""s disease, and proctitis), other noninfectious, inflammatory conditions of the GI tract (microscopic colitis, allergic eosinophilic gastroenteritis, food allergies, pill induced esophagitis, celiac disease, recurrent polyps, and hemorrhoids), and psoriasis, wherein progesterone or a progesterone analog is administered to the patient.
Progesterone analogs for use in the invention include, but are not limited to: acetophenone derivative of 16xcex1, 17xcex1-dihydroxyprogesterone, allyestrenol, chlormadinone acetate, cyproterone acetate, desogestrel, dimethisterone, dydrogesterone, esthisterone, estrenols, ethinylestrenol, ethlestrenol, ethynodiol diacetate, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, norethandrolone, norethindrone, norethindrone enanthate, norethisterone, norethynodrel, norgestimate, norgestrel, 19-nortestosterone, and valerate and caproate esters of progesterone.
In one embodiment of the invention, the progesterone analog is medroxyprogesterone acetate. Other embodiments include medroxyprogesterone and its other salts and derivatives. While not wishing to be bound by any theory, it is believed that during IBD and other noninfectious, inflammatory conditions of the bowel, lymphocytes may infiltrate the bowel, drawn there by a cytokine or other chemotactic or inflammatory mediators. Progesterone and progesterone analogs may inhibit the release of the cytokine or other chemotactic agent from a cell in the bowel, thus decreasing the number of lymphocytes that are recruited to the bowel. Progesterone and progesterone analogs downregulate the Fc receptors in macrophages. The Fc receptor recognizes antibodies or immune complexes present in an inflammatory process, and such stimulation of the Fc receptor is one of the ways that the macrophage is signaled to release TNF-xcex1 and IL-6.
Progesterone analogs with higher xe2x80x9cclassic progestational activityxe2x80x9d, as determined by in vitro binding to the uterus or other uterine activity, can provide more effective treatment in the present invention. The presence and extent of classic progesterone activity are determined by the effect of the compound on the uterus. For example, in the rabbit the extent of the effect on the uterine endometrium is determined. Terenius L., Affinities of progestogen and estrogen receptors in rabbit uterus for synthetic progestogens, Steroids 23:909-919 (1974); Goth A., Medical Pharmacology, C. V. Mosby Co., St. Louis, p. 429 (1966); Duncan M R, et al., An in vivo study of the action of antiglucocorticoids on thymus weight ratio, antibody titre, and the adrenal pituitary hypothalamus axis, J. Steroid Biochemistry 10:245-59 (1979). 17-hydroxyprogesterone and analogs of progesterone that have less progestational classic sex hormone activity may be less effective in the present method. However, derivatives of 17-hydroxyprogesterone that have progestational activity will be effective in the invention.
In one advantageous embodiment, the progesterone or progesterone analog will have low bioavailability, so that much of it will remain in the GI tract, in bowel disorders, or on the skin, for topical psoriasis disorders,;directly treating the diseased tissue. Lower bioavailability may be advantageous because decreased systemic absorption could result in decreased systemic side effects and complications. This could allow patients with chronic conditions to receive treatment for longer periods of time. Although not wishing to be bound by theory, it is believed that the invention may work through a combination of local and systemic effects.
A selective delivery system should provide even more effective treatment. Such a selective delivery system could include an enteric coated tablet or capsule, a low solubility tablet, capsule, suspension, suppository, enema, liquid, foam, cream, gel, ointment, powder, or any of the following forms discussed below. Enteric coatings can be applied to tablets to gain local delivery to various portions of the gastrointestinal tract (for example, upper versus lower). Other coatings can allow for a controlled release of the medication. For example, U.S. Pat. No. 5,458,888, teaches that controlled release dosage forms can be prepared using an external phase of a polyethylene glycol polymer with an average molecular weight of from 3000 to 10000. Additionally, the ""888 patent teaches mixing a drug with certain gel forming polymers, allowing for sustained and controlled release in the stomach. The combination of the drug with a non-chemically cross-linked alkyl-substituted cellulose can also provide sustained release in the stomach, according to the method taught in U.S. Pat. No. 5,582,837.
Other techniques allow for delivery of medication to the lower GI tract. Enteric coating materials include cellulose acetate phthalate or a plasticized cellulose acetate phthalate, and are taught in U.S. Pat. No. 5,686,106. Furthermore, pH sensitive capsules can allow for delivery to the more neutral environment of the lower GI tract, as disclosed in U.S. Pat. No. 5,716,648. This can be accomplished by using a coating which is insoluble in gastric juices of a pH below 4, but soluble in intestinal juice exhibiting a pH from 4 to 7. For example, polyvinyl acetate phthalate (PVAP) results in release of active ingredients in the duodenum. Hydroxypropyl methylcellulose phthalate (HPMCP) resists solubility until the environment achieves a pH of at least 5-6. The HPMCP compounds are available in several forms, some providing protection for tablets up to pH 6 and 7, respectively, for release into the colon.
Low solubility formulations can be achieved by mixing the progesterone or progesterone analog with cyclodextrans according to the method presented in U.S. Pat. No. 4,727,064. These can be used as suspensions, or dried into powders for conversion into tablets, capsules, or other solid dose forms. Certain oils have also been routinely used for suspensions of water insoluble agents to form liquid preparations or gel capsules.
Additionally, the progesterone or progesterone analog can be encapsulated in microspheres by a coating of a cross linked coacervate of gelatin and chondroitin sulfate, allowing for time release of the drug, according to the method taught in U.S. Pat. No. 5,759,582.
Tablets and capsules can be coated with a gum that is broken down by enzymes found in the gut, as disclosed in U.S. Pat. No. 5,656,294. Hydrocolloid gums, obtainable from higher plants, such as guar gum, locust bean gum, gum tragacanth, or karaya gum can be used.
Other strategies for targeted delivery to the colon include those presented in Friend et al, Drug Glycosides: potential prodrugs for colon-specific drug delivery, J. Med. Chem. 28:51-57 (1985); Rubenstein, Microbially controlled drug delivery to the colon, Biopharm and Drug Dispos 11:465-475 (1990); Salyers et al, Cellular location of enzymes involved in chondroitin sulfate breakdown by Bacteroides thetaiotaomicron, J. Bacteriol 143:772-780 (1980). Various strategies for rectal administration of compounds are described in Marshall et al., Putting Rectal 5-Aminosalicylic Acid in its Place: The Role in Distal Ulcerative Colitis, Am. J. Gastroenterology, 95:1628-1636 (2000).
Very specific delivery can be achieved by using an enteric feeding tube to deliver the progesterone or progesterone analog composition directly to the inflamed section of the gastrointestinal tract, according to the method presented in U.S. Pat. No. 5,120,306. This technique works especially well for delivery to the proximal small bowel. It could also be applied to the large bowel, either by using an enteric feeding tube or by using similar tubing entering the gastrointestinal tract rectally. For psoriasis, the progesterone or progesterone analog could be topically applied to the lesion, injected into the lesion, or injected into the body near the lesion.
The progesterone or progesterone analogs used in the methods of the present invention may be formulated in a pharmaceutical composition, which may include carriers, thickeners, diluents, buffers, preservatives, surface active agents, tableting agents, liposomes, or lipid formulations, and the like. The pharmaceutical compositions may also include one or more active ingredients such as antimicrobial agents, antiinflammatory agents, anesthetics, and the like.
The pharmaceutical composition may be administered in a number of ways depending on whether local or systemic treatment is desired, and on the area to be treated. Administration may be topically (including on the skin), rectally (by suppository or enema), intranasally, orally, by inhalation, or parenterally, for example by intravenous drip, subcutaneous, intraperitoneal, intramuscular injection, or injection into an area requiring treatment. The activity and metabolism of the composition should be used as a guide when determining the route of administration.
Formulations for topical, rectal, and intranasal administration may include ointments, lotions, creams, gels, drops, enemas, ointments, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners, and the like may be necessary or desirable. Compositions for oral administration include powders or granules, suspensions or solutions in water or nonaqueous media, capsules, or tablets. Thickeners, flavorings, diluents, emulsifiers, dispersing aids, tableting agents, or binders may be desirable. Formulations for parenteral administration may include sterile aqueous solutions optionally containing buffers, liposomes, diluents and other suitable additives.
Dosing is dependent on the severity and responsiveness of the condition to be treated, with a course of treatment lasting from several days to several months or until a cure is effected or a diminution of disease state is achieved.
For treatment with an oral composition, in tablet form, for example, dosing is as follows. Optimal dosing schedules and dosing amounts can be calculated based on the severity of the disease and the weight of the patient according to the general guidelines below. Dosages and frequencies would be greater for a patient with a more severe disease state or a higher weight. Depending on the formulation or whether local/targeted delivery is employed, slightly lower doses would be appropriate.
One oral dosing schedule is to treat a patient suffering from inflammatory conditions, including but not limited to, inflammatory bowel disease (ulcerative colitis, Crohn""s disease, and proctitis), other noninfectious, inflammatory conditions of the GI tract (microscopic colitis, allergic eosinophilic gastroenteritis, food allergies, pill induced esophagitis, celiac disease, recurrent polyps, and hemorrhoids), and psoriasis, with from about 10 mg to about 5 g, alternatively from about 20 mg to about 4 g, alternatively from about 50 mg to 3 g, alternatively from about 100 mg to 2 g, alternatively from about 500 mg to about 2 g, and alternatively from about 500 mg to about 1 g, total daily dose.
For treatment with a topical composition, applied to the skin as a cream, gel, or lotion, or administered rectally as a cream, foam, enema, or suppository, dosing is as follows. Optimal dosing schedules and dosing amounts can be calculated based on the severity of the disease, the area of skin to be treated (when applied to the skin) or the volume of the rectal administration (when applied rectally). Dosages and frequencies would be greater for a patient with a more severe disease state. Dosages, as percent of active ingredient to vehicle, could be reduced when very large areas of the skin are to be treated, and could be reduced if a larger volume rectal treatment was used (i.e., a larger suppository, for example).
One topical dosing schedule is to treat a patient suffering from inflammatory conditions, including but not limited to, inflammatory bowel disease (ulcerative colitis, Crohn""s disease, and proctitis), other noninfectious, inflammatory conditions of the GI tract (microscopic colitis, allergic eosinophilic gastroenteritis, food allergies, recurrent polyps, and hemorrhoids), and psoriasis, with from about 20 mg to about 4 g, alternatively from about 225 mg to about 1.25 g, alternatively from about 550 mg to 750 mg, alternatively about 650 mg, total daily dose.
Both oral and topical dosing can occur once a day, every other day, three times a week, or twice a week. It can also occur in divided doses, twice, three, or four times a day. One acceptable dosing schedule is once a day. Initial treatment can continue for up to 2 weeks for an acute condition, or about 4 weeks to about 16 weeks for a chronic condition, or alternatively about 8 weeks to about 12 weeks for a chronic condition. Longer therapy may also be needed. Patients can be treated for up to six months, or up to one year. Maintenance treatment can last up to or longer than one year. Patients can be treated on a maintenance basis or on an as needed basis during a problematic episode, depending on the severity of the patient""s condition. Patients can also be treated on a rotating treatment basis, where treatment is provided for a period of time and then the patient is given a drug holiday before treatment resumes again. During the drug holiday, patients may receive no treatment, treatment with another mediation or treatment protocol, or treatment with a reduced dosage. Additionally, patients could receive treatment with a higher dose of the composition until a desired reduced disease state is achieved, and then continued on a lower dose of the composition.